17-{62 -Hydroxy-17-{60 -methyl-5-{60 -androstano{9 3,2-c{9 or{8 2,3-d{9 isoxazoles

ABSTRACT

7-Oxa steroids which may be substituted in the 3-position with a hydroxy or oxo group or in the 2-position with a hydroxymethylene group or in the 2- and 3-positions with a substituent that forms a 5-membered heterocyclic ring, useful as antigonadotropic agents and a method of preparing these 7-oxa steroids from 3-hydroxy Delta 5-steroids including intermediates in this process.

United States Patent [191 Guthrie et al.

[ 17-,B-HYDROXY-l 7-a-METHYL-5-a- ANDROSTANO[3,2-C]OR [2,3-D ]ISOXAZOLES[75] Inventors: Robert William Guthrie, Fairfield;

Richard Wightman Kierstead; Ronald Andrew LeMahieu, both of NorthCaldwell, all of NJ.

[73] Assignee: Hoffmann-LaRoche, lnc., Nutley,

[22] Filed: June 5, 1972 [21] Appl, No.: 259,526

[ 1 Mar. 4, 1975 [56] References Cited FOREIGN PATENTS OR APPLICATIONS45-18664 6/1970 Japan 260/307 D OTHER PUBLICATIONS Guthrie, et 211.,Chemical Abstracts 78:154986 y (1973).

Primary E.\'mninerDonald G. Daus Assistant Examinen-Ralph D. McCloudAttorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe; William H. Epstein[57] ABSTRACT 7-Oxa steroids which may be substituted in the 3- positionwith a hydroxy oroxo group or in the 2- position with a hydroxymethylenegroup or in the 2- and 3-positions with a substituent that forms a 5membered heterocyclic ring, useful as antigonadotropic agents and amethod of preparing these 7-oxa steroids from 3-hydr0xy A' -steroidsincluding intermediates in this process.

3 Claims, N0 Drawings 1'l-B-HYDROXY-17-a-METHYL-5-a- ANDROSTANO[3,2-C]OR[2,3-D]ISOXAZOLES SUMMARY OF THE INVENTION In accordance with thisinvention, it has been discovered that compounds of the formula:

wherein R and R are as above; and R is oxo or lower alkylenedioxy; andthe dotted bond in the A ring can be optionally hydrogenated; are usefulas antigonadotropic agents.

The compounds of formulae I and I-A are prepared from compounds of theformula:

wherein R, is a hydrolyzable ester, R is or hydrolyzable ester; R, ishydrogen, lower alkylor a hydrolyzable ester with the proviso that atleast one of R and R, is other than a hydrolyzable ester.

DETAILED DESCRIPTION OF THE INVENTION The term conventional hydrolyzableester" as used herein denotes the hydrolyzable ester groupconventionally employed in the steroid art to protect hydroxy groups.Among the preferred esters are those from hydrocarbon carboxylic acidsor phosphoric acids and their salts. The term hydrocarbon carboxylicacids" defines both substituted and unsubstituted hydrocarbon earboxylicacids. These acids can be completely saturated or possess varyingdegrees of unsaturation (including aromatic), can be of straight chain,branched chain, or cyclic structure, and preferably contain from I to 12carbon atoms. In addition, they can be substituted by functional groups,for example, hydroxy, alkoxy containing up to 6 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino, halogeno, and the like,attached to the hydro carbon backbone chain. Typical conventionalhydrolyzable esters thus included within the scope of the term and theinstant invention are acetate, propionate, butyrate, valerate, caproate,enanthate, caprylate, pelargonate, acrylate, undecenoate,phenoxyacetate, benzoate, phenylacetate, diphenylacetate,diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate,methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate,adamantoate, glycolate, methoxyacetate,

hemisuccinate, hemiadipate, hemi-BJidimethylglutarate, acetoxyacetate,2chloro-4- nitrobenzoate, aminoacetate, diethylaminoacetate,

piperidinoacetate, B-chloropropionate, trichloroacetate,B-chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzylhydrogen phosphate, sodium benzyl phosphate, cyclohexylammonium benzylphosphate, sodium phenyl phosphate, sodium ethyl phosphate, dip-nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate,cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate,benzyl ocarbomethoxy-phenyl phosphate and the like.

Among the preferred esters are those derived from lower alkanoic acidssuch as acetic acid and halo substituted lower alkanoic acids such astrifluoro acetic acids.

As used herein, the term halogen comprehends all four halogens such aschlorine, fluorine, bromine and iodine. Alkali metal, as used herein,has its usual mean ing and includes such metals as lithium, sodium andpotassium. The term lower alkyl comprehends both straight and branchedchain saturated hydrocarbon moieties having from I to 7 carbon atomssuch as methyl, ethyl, tbutyl, i-propyl, etc.

Lower alkanoic acids comprehend lower alkane car boxylic acidscontaining from 2 to 7 carbon atoms such as acetic acid, butyric acidand the like. The term halo substituted lower alkanoic acids includeslower alkanoic acids containing from 2 to 7 carbon atoms which are mono,di or tri substituted with a halo group. Among the preferred halosubstituted lower alkanoic acids are included trifluoroacetic acid.

The term lower alkylenedioxy", as used herein, comprehends loweralkylenedioxy moieties containing from 2 to 4 carbon atoms where the twooxygens are attached to the same or different carbon atoms of analkylene chain such as ehtylenedioxy, isopropylidenedioxy, etc. The termphenyl lower alkyl designates phenyl lower alkyl moieties wherein loweralkyl is defined as above. Among the preferred phenyl lower alkylmoieties are included, benzyl, phenethyl and phenpro- Py The compoundsof formula I above are characterized by a high degree ofantigonadotropic activity. Thus, the compounds of formula 1 above can beadministered internally, for example, orally or parenterally, withdosage adjusted to individual requirements in the form of conventionalpharmaceutical preparations; for example, they can be administered inconventional pharmaceutical solid or liquid forms such as tablets,pills, capsules, solutions, suspensions, emulsions or the like. Thesepharmaceutical preparations can contain conventional pharmaceuticalcarriers and excipients such as water, talc, corn starch, polyalkyleneglycols, emulsifying agents, buffering agents, agents for the adjustmentof osmotic pressure, Vaseline and the like. Also, compositionscontaining an active ingredient of this invention can be subjected toconventional pharmaceutical processes such as sterilization or the like.Also, the pharmaceutical compositions of this invention can containother active ingredients. Moreover, the endocrinologically activecompounds can be administered as feed additives, and for this purposecan be admixed with conventional animal feeds or conventional animalfeed premixes. Though, as indicated, the dosage of theendocrinologically useful compounds of this invention should be adjustedto individual needs, i.e., the compounds of formula 1 above can beadministered internally in daily dosage regimens of from about 1 mg./kg.to about 10 mg./kg. per day. The dosages can be administered in unit ordivided dosage forms.

The usefulness of the compounds of formula I as antigonadotropic agentsis indicated in animals. For example, when these compounds areadministered orally for 21 consecutive days to immature rats in a sesameoil solution, there results a decrease in the testes weight of the rats.For example, when compounds such as7-oxal7B-hydroxy-l7a-methyl-5a-androstano-[3,2-c]- pyrazole and 7-oxal7B-hydroxyl 7B-methyl-5aandrostan-3-one, 3-ethylene ketal wasadministered orally to immature rats for 21 consecutive days in sesameoil solution at a dosage level of l mg./kg. per day there resulted adecrease of about 17 percent in the weight of the rats testes ascompared to the control rats which were treated with pure sesame oil.

Among the preferred compounds of formula I are included compounds of theformula:

wherein R is hydroxy, lower alkanoyloxy, preferably acetyloxy, or halolower alkanoyl. Still another preferred embodiment of the compounds offormula I are compounds of the formula:

wherein R and R are as above; R is hydrogen. lower alkanoyl or halolower alkanoyl; and R is hydrogen or lower alkyl. When R in the compoundof formula l-Bi is lower alkyl, the preferred groups are methyl orethyl. When R is alkanoyl, the preferred group is acetyl.

Among the preferred compounds of formula l-A are included compounds ofthe formula:

I-Ai

wherein R R and R are as above; and compounds of the formula:

I-Aii wherein R and R are as above.

The compounds of formula 1 above are prepared from the compounds offormula ll via an intermediate of the formula:

III

wherein R is lower alkylenedioxy; R is hydroxy o'r acetyl ketalized inthe 20-position with lower alkylenedioxy; R is hydrogen, lower alkyl.hydroxy. with the proviso that at least one of R and R is other thanhydroxy.

The intermediate of formula lll can be prepared by the followingreaction scheme:

LA/ (b) R]! CH3 W (d) O /l\/ A 3 n V l l l (e) l O O h it "it VI 0 VIIIII wherein R, R R R R and R are as above; R

is trifluoroacetyloxy or hydroxy; R" is acetyl or trifluoroacetyloxy; R,is hydrogen, lower alkyl, or trifluoroacetyloxy; with the proviso thatwhen R" is trifluoroacetyloxy, R is hydrogen or lower alkyl.

The compound of formula II is a compound wherein the free hydroxy groupswhich may be present in the 3 and l7-positions are protected byesterification. In esterifying a compound of formula II which has freehydroxy groups at the 3 and l7-positions, any conventional esterifyingagent can be utilized such as a lower alkanoic acid anhydride or halosubstituted lower alkanoic acid anhydride. Where the compound to be protected contains a free hydroxy group at both the 3 and l7-position, itis generally preferred to utilize trifluoroacetic acid anhydride as theesterifying agent, since in the latter steps, hydrolysis of thetrifluoroacetoxy groups will occur first in the 3-position. Therefore,the use of trifluoroaeetic acid anhydride will provide a 3,l7-diesterwhich can be selectively hydrolyzed in the latter steps, to a 3hydroxy-l7-trifluoroaeetate ester. While other esterifying agents can beutilized, best re sults fora selective hydrolysis is accomplished byutilizing trifluoroacetic anhydride as the esterifying agent. Theestcrification reaction is generally carried out in the presence of anamine base, such as pyridine, triethylamine, etc. In carrying out thisreaction, temperatures of from 30to 25C. are generally utilized.

The conversion of compounds of formula II to compounds of the formula IVvia reaction step (a) is carried out by treating the compound of theformula IV with a chromate oxidizing agent. Any of the conventionalehromate oxidizing agents such as chromium trioxide pyridine complex,sodium chromate, tertiary butyl chromate, etc., can be utilized.Generally, it is preferred to utilize t-butyl chromate as the oxidizingagent. Generally, this reaction is carried out in an inert organicsolvent with a halogenated hydrocarbon solvent, such as carbontetrachloride and methylene chloride being preferred. In carrying outthis reaction, temperature and pressure are not critical, and thisreaction can be carried out at room temperature and atmospheric pressureor at elevated temperatures and pres sures. Generally, it is preferredto carry out this reaction at a temperature of from 20to C.

The compound of formula IV is converted to the compound of formula V,via reaction step (b), by catalytically hydrogenating the compound offormula IV. Any conventional means of catalytic hydrogenation can beutilized to convert the compound of the formula IV to the compound offormula V. Among the preferrred catalysts for use in this reaction arethe noble metals such as palladium or platinum. Generally, these noblemetals are utilized with a support material such as carbon or charcoal.The preferred catalyst for use in carrying out the reaction of step (b)is palladium on carbon.

When the ester group on the 3 and l7-positions in the compound offormula V is other than trifluoroacetate, the compounds of formula V canbe hydrolyzed by conventional means to produce free OH groups at boththe 3 and l7-positions. The hydrolyzed compound can be reesterified byconventional means to the compound of formula V-A so that the protectinggroups on both the 3 and l7-positions are trifluoroacetate. By providinga trifluoroacetate protecting group, this protecting group is removed,in later steps of this process utilizing very,

weak conditions without affecting the lactone structure which is presentin the compounds in the later steps of the process of this invention.

In the compound of formula V where the hydroxy groups in the 3 andl7-positions are protected by a trifluoroacetate group, the compound offormula V can beselectivvely hydrolyzed to the compound of formula V-'Aso that the hydroxy group in the 3-position is free, whereas the hydroxygroup in the l7-position is protected by a trifluoroacetate group.

The compound of formula V-A is converted to the compound of the formulaVI via reaction step (d), by Baeyer-Villager oxidation with an organicperacid. Any conventional organic peracid can be utilized in carryingout this oxidation. Among the conventional organic peracids are includedperacetic acid, perphthalic acid, etc., with m-chloroperbenzoic acidbeing preferred. Generally, this reaction is carried out at temperaturesfrom 10C. to reflux in an inert organic solvent. Any conventional inertorganic solvent can be utilized. The preferred inert organic solventsare the halogenated hydrocarbon solvents with chloroform beingespecially preferred.

The compound of formula VI where R, is trilluoroacetoxy can behydrolyzed with a weak base such as an alkali metal bicarbonate toconvert R, into a free hydroxy group. The use of a weak. base willselectively hydrolyze only the 3-trilluoroacetate group.

The compound of formula Vll, when reacted with a ketalizing agent suchas a lower alkylenc glycol in the presence of an acid catalyst such aspara-toluene sulfonic acid produces a compound of the formula IIIwherein the 3-oxo group is ketalized. If the compound of formula Vll hasa 2(l-oxo group, these groups are also ketalized in this reaction. Incarrying out the reaction of step (f), any conventional lower alkyleneglycol such as ethylene glycol, propylene glycol, etc., can be utilizedas the ketalizing agent. The reaction of step (f) is carried out byutilizing conventional ketalizing procedures well known in the art.

Where R" in the compound of formula Vll is trifluoroacetyloxy, thecompound of formula Vll is hydrolyzed in the aforementioned manner afterketalization to produce a compound of the formula III where R ishydroxy.

If during the ketalization reaction of step (f), the

7-oxo group on the compound of formula III becomes ketalized, this ketalgroup can be selectively removed by treatment with magnesium sulfate inan inert organic solvent wetted with water.

In accordance with this invention, the compound of formula III isconverted toa compound of the formula:

wherein R R and R are as above; and R is phenyl or lower alkyl. When Ris lower alkyl, the compound of formula X is prepared via the followingreaction scheme:

CH3 R7 CH: W /Y 0 III in R0 ornlm OH XIII l6) Tie CH: R7

CH3 l its { oinor :-1tw' wherein R R and R are as above; and R is loweralkyl. The reaction of step (h) is carried out by reacting the compoundof the formula III with a lower alkyl lithium such as methyl lithium ora lower alkyl magnesium halide.

The reactions of step (h) are suitably conducted in an inert organicsolvent such as, for example, hydrocarbon ethers, such astetrahydrofuran, diethyl ether, dioxane or the like, or aromatichydrocarbons such as benzene or the like. In carrying out the reactionof step (h), temperature and pressure are not critical, and the reactioncan be carried out at room temperature and atmospheric pressure.However, if desired, elevated or reduced temperatures can be utilized.Generally, it is preferred to carry out this reaction at a temperatureof from 10 to +20C. It is particularly surprising that a compound of theformula XIII is produced when a compound of the formula III is reactedwith a lower .alkyl lithium or lower alkyl magnesium halide. This istrue since the compound of the formula XIII which is formed by thisreaction, contains a potential carbonyl group which could additionallyreact with phenyl lithium to produce addition across the carbonyl group.However, it has been unexpectedly discovered that when the compound offormula III is reacted with lower alkyl lithium or lower alkyl magnesiumhalide, only one mole of the alkyl lithium or lower alkyl magnesiumhalide is reacted per mole of the compound of formula III, producingonly a single addition across the 7-carbonyl group of formula III.

The compound of the formula XIII is converted to the compound of formulaX-A by treating the compound of the formula XIII with an organicperacid. Any conventional organic peracid can be utilized in carryingout this reaction. Among the conventional organic peracids which can beutilized are included perbenzoic acid, m-chloroperbenzoic acid,peracetic acid and monoperphthalic acid. In accordance with a preferredembodiment, monoperphthalic acid is utilized to carry out the reactionof step (i), since oxidation with monoperphthalic acid produces thecompound of formula X-A directly form the compound of formula XIIIwithout any undesired side products. It has been found that when otherorganic peracids are utilized to oxidize the compound of formula XIII toX-A, the compound of formula X-A is formed in combination with otherside products. These side products can be separated from the compound offormula X-A by conventional separating techniques such chromatography.However, when monoperphthalic acid is utilized as the oxidizing agent,only the compound of formula X-A is formed, thereby eliminating thenecessity for separating any side products. In carrying out the reactionof step (i), temperature and pressure are not critical and anytempcraturc of from 0to I()()C. can be utilized. lfdesired, the reactionofstep (i) can be carried out in an inert organic solvent. Any of theconventional inert organic solvents, such as those mentionedhereinbefore can be utilized.

Where R in the compound of formula X is a phenyl group, the compound offormula X is prepared via the following reaction steps:

III

L Yfm B A Ra CHa l wherein R R and R are as above; and R is phenyl.

The compound of formula XV is prepared via reaction step (j) by reactingthe compound of formula III with phenyl lithium or a phenyl magnesiumhalide.

The reaction of step (j) is carried out in the same manner utilizing thesame reaction conditions that were described in connection with step(h). The reaction of a compound of the formula III withphenyl lithium orphenyl magnesium halide to produce a compound of the formula XV wassurprising, since the phenyl lithium or the phenyl magnesium halide onlyreacts once with the carbonyl group in the compound of the formula III.No reaction occurred between the phenyl lithium or phenyl magnesiumhalide and the carbonyl group in the compound of the formula XV.Therefore, by reacting phenyl lithium or phenyl magnesium halide with acompound of the formula III, only one mole of phenyl lithium or phenylmagnesium halide reacts with one mole of the compound of the formula IIIto produce a compound of thc formula XV.

The compound of the formula XV is reacted with organic peracid viareaction step (k) to produce a compound of the formula XB. The reactionof step (k) is carried out in the same manner and utilizing the sameconditions as described in connection with reaction step (i). Incarrying out this reaction, monoperphthalic acid is the preferredorganic-peracid since its use prevents the formation of any undesiredside products.

The compound of the formula X above can be converted to the compound offormula I above where R is hydrogen and R is lower alkylenedioxy by thefollowing reaction scheme:

I: 0H: l

wherein R R and R are as above.

The compound of formula X above is converted to the compound of formulaXVI above via reaction step (1) by ester hydrolysis. Any conventionalmethod of ester hydrolysis can be utilized in carrying out the reactionof step (1). Generally, it is preferred to utilize a strong base such asan alkali metal hydroxide to carry out this hydrolysis.

The compound of formula XVI above is converted to the compound offormula XVII by reacting the compound of formula XVI with a compound ofthe formula:

XVI

XVII

R halo XVIII wherein R is phenyl sulfonyl, lower alkyl sulfonyl andlower alkyl substituted phenyl sulfonyl.

Among the compounds of formula XVIII, tosyl chlo ride and methanesulfonyl chloride are preferred. The reaction of step (m) is carried outby reacting the compound of formula XVI above with the compound offormula XVIII above in a basic reaction medium. In accordance with apreferred embodiment of this invention, this reaction is carried out inan organic amine base such triethylamine, pyridine, etc. The organicamine base can act as the solvent medium for the reaction. In carryingout this reaction, temperature and pressure are not critical and thisreaction can he carried out at room temperature and atmosphericpressure. Generally, it is preferred to carry out this reaction at atemperature of from 0 to 30C.

If, in the compound of formula XVII, R, is a ketalized acetyl group,this ketalized acetyl compound can, if desired, be converted to thecorresponding ZO-keto compound without effecting the ketal group on the3- position by treating the compound of formula XVI or XVII above with aweak acid at temperature of from 2()to 20C. Among the weak acids, oxalicacid or a Lewis acid such as boron trifluoridc is preferred. Generally,this reaction is carried out in an inert organic solvent. Anyconventional inert organic solvents such as methanol, ethanol,chloroform, carbon tetrachlo ride, tetrahydrofuran, etc., can beutilized. If desired, when one of R or R in the compounds of formulaXVII is hydroxy, this hydroxy group can be esterified to form ahydrolyzable ester group in the manner de- XVII XIX

on: k/ 110 021g (L llitl' Il wherein R and R are as above; R, is hydroxyor acetyl; R is hydrogen, hydroxy or lower alkyl with the proviso thatone of R or R is other than hydroxy; and R and R taken together withtheir attached carbon atoms form a pyrazole or isoxazole ring.

In reaction step (ii), the ketal group in the 3-position of the compoundof formula XVII is cleaved by conventional means such as treatment witha strong acid, particularly p-toluene sulfonic acid, sulfuric acid, etc.Furthermore, if R is acetyl, which is ketalized in the position with alower alkylenedioxy group, treatment with a strong acid produces thecompound of formula XIX wherein R; is acetyl having a free oxo group inthe 20-position.

The compound of formula XIX above is converted to the compound offormula XX above by treating the compound of formula XIX with a loweralkyl ester of formic acid such as methyl formate or ethyl formate.Generally, the reaction of step (0) is carried out in the presence of analkali metal hydride or an alkali metal lower alkoxide. Any conventionalalkali metal hydrode such as sodium hydride, potassium hydride, etc.,can be XXI.

utilized. Alternatively, any conventional alkali metal lower alkoxidesuch as sodium methoxide. potassium ethoxide, etc., can be utilized.This reaction is generally carried out in an inert organic solvent,preferably an organic amine solvent, such as diethylamine.triethylamine, pyridine, etc. In carrying out this reaction. temperatureand pressure are not critical and this reaction can be carried out atroom temperature and atmospheric pressure. However, if desired, higheror lower temperatures and pressures can be utilized. Generally. thisreaction can be carried out at any temperature of from 0C. to the refluxtemperature of the reaction medium.

When R and R in the compound of formula XXI form with their attachedcarabon atoms a pyrazole ring, this compound can be prepared by reactingthe compound of formula XX with hydrazine hydrate. Generally, thisreaction can be carried out in an inert organic solvent. Anyconventional inert organic soilvent can be utilized carrying out thisreaction. Among the preferred inert organic solvents are included loweralkanol solvents such as methanol, ethanol, etc., and hydrocarbonsolvents such as benzene, toluene, etc. In carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and atmospheric pressure. Generally,this reaction is carried out in any temperature of from 20C. to thereflux temperature of the reaction medium,

When R and R in the compound of formula XXI form an isoxazole ring withthe nitrogen adjacent the 3-position, this compound is formed byreacting the compound of the formula XX with an acid addition salt ofhydroxylamine utilizing an organic amine base, such as pyridine as thesolvent. On the other hand, where R and R in the compound of formula XXIform an isoxazole ring with the oxygen adjacent the 3-position, thiscompound is formed by reacting the compound of formula XX with an acidaddition salt of hydroxylamine utilizing a lower alkanoic acid such asacetic acid as the solvent. Generally, the alkali metal salt of thelower alkanoic acid is present in the reaction medium in combinationwith the alkanoic acid. In forming the isoxazole derivative of formulaXXI, pyridine is the preferred organic amine base. Among the preferredsalts of hydroxylamine are included the sulfuric acid and hydrochloricacid salts. In carrying out the reaction to produce the isoxazolederivative of formula XXI, temperatture and pressure are not criticaland this reaction can be carried out at any temperature of from 20C. tothe reflux temperature of the reaction medium.

A a and 0:" compound of formula l-A can be produced from the compound offormula XIX above via the following reaction scheme:

XIX

R CH3| CH3 /Y\ I XXIII CH3 R1 CI Ia l L i/V XXIV wherein R, R R and Rare as above.

The compound of formula XIX is converted to the compound of the formulaXXIII by conventional means such as treating the compound of formula XIXwith a dehydrogenating agent such as dichlorodicyanoben zoquinone (DDQ).Prior to converting the compound of formula XIX-A to the compound of theformula XXIII, any free hydroxy groups contained within the substituentR or R should be esterified. The esterification can be carried out byconventional means. If desired, these ester protecting groups can beremoved from the compound of formula XXIII by treating the compound offormula XXIII in the conventional manner with an alkali metal base suchas sodium hydroxide, potassium hydroxide, sodium bicarbonate, etc. Ifdesired, the 0x0 groups such as at the 3 and -positions in the compoundof formula XXIII, can be ketalized to form a 3 and 20-loweralkylenedioxy derivative of the compound of formula XXIII. Thisketalization can be carried out in the manner described hereinbefore.

The compound of formula XXIII can be converted to the compound offormula XXIV by hydrogenation utilizing a soluble catalyst such astristriphenylphosphine chlororhodium. Any of the conditions conventionalin hydrogenation can be utilized in carrying out the conversion ofcompounds of the formula XXIII to the compound of the formula XXIV. Ifdesired, the 0x0 groups such as at the 3 and 20-positions in thecompound of. formula XXIV can be ketalized in the manner describedhereinbefore to form a 3 and 20-lower alkylenedioxy derivative of thecompound of the formula XXIII.

The compounds of formula XIX, XX, XXI, where one of R or R is a hydroxygroup can be esterified with a conventional hydrolyzable esterprotecting group as described hereinbefore. On the other hand, where Rin the compound of formula XIX or XX is acetyl, the 20-oxo group can, ifdesired, be ketalized by conventional means such as describedhereinbefore.

The 3-oxo group in the compounds of formulae XIX and XX can, if desired,be ketalized by conventional means.

The following examples are illustrative but not limitative of thepresent invention. In the examples, all temperatures are in degreesCentigrade and the ether is diethyl ether.

EXAMPLE 1 Preparation of 3B, l7B-dihydroxyl 7a-methylandrost-5-ene,

' 3 l 7-ditrifluoroacetate To a stirred solution of 3B,l7B'dihydroxy-l7ormethylandrost-S-ene g.) in dry pyridine (750 ml.)previously cooled to 0 was added trifluoroacetic anhydride ml.) at sucha rate that. the temperature did not exceed 05. The reaction mixture wasmaintained at ice bath temperature for an additional 60 minutes then itwas poured slowly into an ice water mixture (3 liters) containing 37percent by weight aqueous hydrochloric acid (750 ml.). The off-whiteprecipitate was removed by filtration washed well with water and airdried to give 3B, l7B-dihydroxy-l7a-methylandrost- S-ene,3,17-ditrifluoroacetate, m.p. I36-I38C.

EXAMPLE 2 Preparation of 3,8, I 7/3-dihydroxyl 7a-methylandrost-S-en-7-one,

3,17-ditrifluoroacetate To a stirred solution of3B,l7fi-dihydroxy-l7ozmethyIandrost-S-ene, 3,17-ditrifl1ioroacetate(39.5 g.) in carbon tetrachloride (400 ml.) containing acetic acid (75ml.) and acetic anhydride (20 ml.) at 60 was added a mixture of t-butylchromate in carbon tetrachloride (250 ml.; equivalent to 46 g. of CrOacetic acid (75 ml.) and acetic anhydride (20 ml.). The mixture wasstirred at 6070 for 18 hours then cooled to room temperature filteredand the filtrate added slowly to a stirred solution of oxalic acid (100g.) in water 1 liter). After 30 minutes, the layers were separated andthe organic layer was washed with water twice and brine twice. The dried(Na SO organic extracts were percolated through a short column of silicagel and then evaporated to give3B,I7/3-dihydroxy-I7amethylandrost-5-en-7-one, 3,1'7-ditrifluoroacetate, as a crude product. This product was crystallizedfrom 100 ml. of a diethylether-hexane mixture (1 to 4 parts by volume)to give 3,8,l7B-dihydroxy-l7amethylandrost 5-en-7-one,3,17-ditrifluoroacetate, m.p. l45l48 C.

EXAMPLE 3 Preparation of 3 B, l 7B-dihydroxyl7a-methyl-5a-androstan-7-one,

l7-trifluoroacetate.

A solution of 313,17,8-dihydroxy-l7a-methylandrost- 5-en-7-one,3,17-ditrifluoroacetate (61 g.) in ethyl acetate (500 ml.) washydrogenated over 4.5 g. of 10 percent by weight of palladium oncharcoal (1 22, p=7 60 mm/I-Ig). After the absorption of 1 equivalent ofhydrogen (about 1 hour) the rate of hydrogenation decreased markedly andthe reaction was stopped. The catalyst was removed by filtration throughdiatomaceous silica and the filtrate was evaporated to dryness to give62 g. of a colorless oil that resisted attempts to crystallize it. Thereduced material was dissolved in a mixture of methanol (300 ml.) andtetrahydrofuran (100 ml.) and a solution of potassium bicarbonate (35g.) in water (100 ml.) was added. The mixture was stirred for 60 minutesthen diluted with water and extracted with methylene chloride. Thecombined organic layers were dried (MgSO evaporated to dryness and theresidue was crystallized from methylene 15 chloride-hexane (l to 4 partsby volume) to give 3,8, 17,8-dihydroxy- 1 7a-methyl-Sa-androstan-7-one,l7- trifluoroacetate, m.p. l64l66C.

EXAMPLE 4 Preparation of 3,8,17B-dihydroxy-17a-methyl-7a-oxa-5a-B-homoandrostan-7-one, l7-trifluoroacetate A solution of33,17B-dihydroxy-l7a-methyl-5aandrostan-7-one, l7-trifluoroacetate (39g.) and mchloroperbenzoic acid (85 percent, 40 g.) in chloroform washeated under reflux for 3 hours. The reaction mixture was cooled to roomtemperature then washed with 5 percent by weight aqueous sodiumbisulfite solution twice, with saturated sodium bicarbonate solutiontwice and with water once. The combined organic layers were dried (Na SOevaporated and the residue crystallized from methylene chloride diethylether (1 to 4 parts by volume) to give 3B,]7B-dihydroxy-l7amethyl-7a-oxa-5a-B -homoandrostan-7-one, l7- trifluoroacetate, m.p. 187-188C.

EXAMPLE 5 Preparation of tane-3,7-dione, l7-trifluoroacetate.

A solution of 33,17B-dihydroxy-l7a-methyl-7a-oxa-5oz-B-homoandrostan-7-one, l7-trifluoroacetate (39 g.) in acetone (100ml.) was cooled to To the stirred solution Jones reagent* (40 ml.) wasadded and the reaction mixture was allowed to stir at 05 for minutes.Isopropanol (50 ml.) was added and the reaction was stirred for anadditional 5 minutes. The reaction mixture was diluted with water (4liters) and the resulting precipitate was collected by filtration thendissolved in methylene chloride, dried (MgSO and evaporated in vacuo togive 17,8-hydroxy-17a-methyl- 7a-oxa-5a-B-homoandrostane-3,7-dione, l7-trifluoroacetate *chromic acid and sulfuric acid in water EXAMPLE 6Preparation of17,8-hydroxy-l7a-methyl-7a-oxa-Sa-B-homoandrostane-3,7-dione, 3-ethyleneketal, l7-trifluoroacetate.

A solution of l7,8-hydroxy-l7a-methyl-7a-oxa-5a-B-homoandrostane-3,7-dione, 17-trifluoroacetate (2.4 g.) andp-toluenesulfonic acid (100 mg.) in benzene ml.) containing ethyleneglycol (2.4 ml.) heated under reflux for 3 hours. The water was removedas it was formed by means of a Dean-Stark trap. The mixture was cooledand poured into an ice cold sodium bidroxide solution. A sufficientamount of methanol was added to make the reaction homogenous and after 5minutes 10 ml. of ethyl acetate was added. The reaction mixture wasconcentrated in vacuo to 100 ml. 5 and then was diluted with water. Theresulting precipitate was collected by filtration, then washed withwater and air dried. Crystallization from diethyl ether-hexane (l to 5parts by volume) affordedl7B-hydroxy-l7amethyl-7a-oxa-5a-B-homoandrostane-3,7-dione, 3- ethyleneketal, m.p. 211-212 EXAMPLE 8 Preparation of5-(2-benzoylmethyl-4,4-ethylenedioxy-l-methyl-lcyclohexanyD-l,7a-dimethylhexahydroindan:l ,4-diol To a stirred solution of17,8-hydroxy- I 7a-methyl-7aoxa-5a-B-homoandrostane-3,7dione, 3-ethyleneketal (13.3 g.) in dry tetrahydrofuran (400 ml.) previously cooled to 0was added 48 ml. of a 2N solution of phenyl lithium in benzene diethylether (75:25 by volume). The ice bath was removed and the mixture wasallowed to stir at room temperature for 60 minutes then it was pouredover ice and extracted with ethyl acetate. The organic layers werewashed with water, then dried (Na SO and evaporated to give a colorlessoil. Filtra tion through a short column of Alumina (Woelm, neutral,grade III) furnished 5-(2-benzoylmethyl-4,4-ethylenedioxy-l-methyl-l-cyclohexanyl)-l,7adimethylhexahydroindan-l,4-diol.

EXAMPLE 9 Preparation of 5-(2-benzoyloxymethyl-4,4-ethylenedioxy- 1-methyl- 1 cyclohexanyl)-l,7a-dimethylhexahydroindan-l,4-diol.

To a solution of 5-(2-benzoylmethyl-4,4- ethylenedioxy- 1 -methyl- 1-cyclohexanyl)- 1 ,7adimethylhexahydroindan-l ,4-diol (15 g.) inchloroform (500 ml.) was added 250 ml. was added 250 ml. of a 0.5 Nsolution of monoperphthalic acid in diethyl ether. The mixture wasallowed to stand at room temperature for 3 hours then was washed with 1Nsodium hydroxide solution and with brine. The dried (MgSO organic layerswere evaporated to give 5-(2- benzoyloxymethyl-4,4-ethylenedioxy- 1-methyl- 1 cyclohexanyl )-l ,7a-dimethylhexahydroindanl ,4-diol as anoil. Chromatography on a column of silica gel (300 g.) furnished5-(2-benzoyloxymethyl-4,4-ethylenedioxy-l-methyl-l-cyclohexanyl)-l-7adimethylhexahydroindan-l,4-diolas a pure product.

EXAMPLE 1O carbonate solution. The layers were separated and the,

organic layer was washed with brine, then dried (Na S0 and concentratedto dryness. The resulting residue was crystallized from methanol to give17,8- Hydroxyl 7a-methyl-7a-oxa-5a-B-homoandrostane- 3,7-dione,3-ethylene ketal, l7-trifluoroacetate, m.p. l87-l88C.

EXAMPLE 7 Preparation of l7B-hydroxyl 7a-methyl-7a-oxa-5a-B-homoandrostane-3,7-dione, 3-ethylene ketal To a stirred solution of17B-hydroxy-l 7a-methyl-7aoxa-Sa-B-homoandrostane-3,7-dione, 3-ethyleneketal, l7-trifluoroacetate (27 g.) in tetrahydrofuran previously cooledto 0 was added 57 ml. ofa 1N sodium hy- Preparation of5-(2-hydroxymethyl-4,4-ethylenedioxy- 1 -methyl- 1 cyclohexanyl)-l,7a-dimethylhexahydroindan-l ,4-diol EXAMPLE 26 Preparation of3,8,17a-dihydroxy-a-pregnan-7,20 -dione To a solution of 39.6 g. of3,8,17a-dihydroxy-5a- Rt 9-q qns disse a n .00 QLQBLQKEHQ and 500 ml. ofmethanol under a nitrogen atmosphere at room temperature was added 450ml. of 1.0 N sodium hydroxide dropwise over 30 minutes. After stirringat room temperature for 3% hours, 200 ml. of 3 N HCl was added and mostof the solvent was removed in vacuo. Water was added and the resultantsolid was filtered and air dried to give3B,17oz-dihydroxy-5apregnan-7,20-dione.

EXAMPLE 27 Preparation of 3B, 1 7a-dihydroxy-5a-pregnan-7,20-dionebistrifluoroacetate.

To 0.7007 g. of 313,17a-dihydroxy-5a-pregnan-7,20- dione in ml. ofanhydrous pyridine cooled in an ice bath was added 0.87 ml. oftrifluoroacetic anhydride. After stirring for 1 hour at 3, the yellowsolution was added dropwise to 10 ml. of concentrated l-lCl and ice withstirring. The resultant solid was removed by filtration, dissolved inbenzene and passed through a column of 16 g. of silica gel. Elution with200 ml. of 5 percent by volume ethyl acetate in benzene andconcentration EXAMPLE 13 Preparation of 5-(2-hydroxymethyl-4,4-ethylenedioxy- 1 -methy1- lcyclohexanyl)-l,7a-dimethylhexahydroindan-l,4-diol To a solution of1,5-dihydroxy-8.8-ethylenedioxy- 1.5.1001, 12a-tetramethyl perhydro-1H-benz-[d]- ideno-[4,5-b]-oxepin 15.7 g.) in chloroform (400 ml.)was added 400 ml. of a 0.65 N solution of monoperphthalic acid indiethyl ether. The mixture was allowed to stand at room temperature for3 hours then was washed with a 1N sodium hydroxide solution and withbrine. The combined organic extracts were dried (MgSO and evaporated invacuo to give 5-(2-aeetoxymethyl-4,4-ethylenedioxy-1-methyl-l-cyclohexanyl)-1.7adimethylhexahydroindan-1,4-diolas a colorless oil.

A solution of5-(2-acetoxymethyl-4,4-ethylenedioxyl-methyl-1-cyclohexanyl)-1,7a-dimethylhexahydroindan-1,4-diol(12.3 g.) in ethanol (500 ml.) containing ml. of 10N sodium hydroxidewas refluxed overnight. The reaction mixture was concentrated in vacuothen diluted with water and extracted with methylene chloride. Thecombined organic layers were washed with water, dried (Na SO andevaporated under reduced pressure to give 5-(2-hydroxymethyl-4,4-ethylenedioxy-l-methyl-l-cyclohexanyl)-1,7adimethylhexahydroindan-l.4-diol.

EXAMPLE 14 Preparation of 7-oxa-l 'lfi-hydroxy- 17a-methyl-Sa-androstan-3-one A solution of7-oxa-l7B-hydroxy-l7a-methyl-5aandrostan-3-one, 3-ethylene ketal (61 g.)in tetrahydrofuran (800 ml.) and 1N aqueous hydrochloric acid (100 ml.)was allowed to stand at room temperature for 18 hours. The reactionmixture was concentrated, di-

luted with water and the resulting solids were filtered. washed withwater and dried to give 52.3 g. of 7-oxa-17,8-hydroxy-17a-methyl-5oz-androstan-3-one. Crystallization of a smallamount from methylene chloride diethyl-ether gave the analytically purematerial, mp. 186188C.

EXAMPLE 15 Preparation of 7-oxa-2-hydroxyethylene-17B-hydroxy-l7a-methyl- 5a-androstan-3-one To a solution-of7-oxa-l7B-hydroxy-17a-methyl-5aandrostan-3-one (4.1 g.) in dry pyridineml.) was added freshly distilled ethyl formate (7.5 ml.) followed byfreshly prepared sodium methoxide (1.38 g.). The reaction mixture wasstirred at room temperature overnight then was poured into ice and watercontaining acetic acid (75 ml.). The resulting mixture was extractedwith methylene chloride (3 X ml.). The combined organic layers werewashed once with water and then 6 times with 100 m1. portions ofa 2percent potassium hydroxide solution. The combined basic extracts werewashed once with diethyl-ether and then were acidified with acetic acid(20 ml.). The resulting slightly yellow precipitate was washed withwater and air dried to give a crude product. Crystallization of thiscrude product from benzene-hexane (1 to 4 parts by volume) (usingmethylene chloride to initially dissolve the material) gave the7-oxa-2-hydroxymethylene-17B- hydroxy-l 7a-methyl5a-androstan-3-one,m.p. 235238C.

EXAMPLE 16 Preparation of 7-oxa-l7B-hydroxy-17a-methyl-5a-androstanol3,2c -pyrazo1e 7-Oxa-17B-hydroxy-l 7a-methyl-5a-androstan-B-one. 3ethyleneketal Tablet Formulation 7'oxa-l7/3hydroxy-17a-methyl- Per Tablet5a-androstan-3-one, 3-ethy1ene ketal 2.55 mg.

Dicalcium phosphate. unmillilled 232.45 mg.

Corn Starch 12.50 mg.

Magnesium Stearate 2.50 mg. Total Weight 250.00 mg.

Procedure:

1. 7-oxal 7,8-hydroxyl 7a-methyl-5a-androstan- 3-one. 3-ethylene ketaland corn starch were blended in a suitable size mixer.

2. The mix was then blended with an equal quantity of DicaleiumPhosphate.

3. The mixture was blended for 5 minutes with the balance of theDicalcium Phosphate and magnesium stearate.

4. The mixture was then compressed.

EXAMPLE 18 Tablets were prepared in the same maner as in Examb lszsss h-w- 5- 1mm- W- EXAMPLE 1 1 Preparation of 7-oxaljB-hydroxy- I7a-methyl-5 a-androstan-3-one, 3-ethylene ketal A solution is preparedby dissolving 7.5 g. of -(2- hydroxy methyl-4,4-ethylenedioxyl'-methyllcyclohexanyl)- l ,7a-dimethylhexahydroindan-l ,4-diol in dry pyridine(75 ml.) and p-toluene-sulfonyl chloride (7.5 g.) was added. Thesolution was stirred at room temperature for 4 hours then was poured inan icewater mixture containing 75 ml. of concentrated hydrochloric acid.The resulting mixture was quickly extracted with methylene chloride andthe organic layers were washed with 1N aqueous sodium hydroxide solutionand with brine. The dried (MgSO organic extracts were evaporated to give7.2 g. of a solid that was essentially homogenous by tlc. Twocrystallizations from methanol gavethe pure7-oxa-l7,Bhydroxy-l7amethyl-5a-androstan-3-one, 3-ethylene ketal, m.p.199-200C.

EXAMPLE 12 Preparation ofl,5-dihydroxy-8,8-ethylenedioxy-1,5,10a,l2atetramethyl per-hydro-lH-benz[d]-indeno-[4,5-b]-oxepin To a stirred solution of l7B-hydroxyl7a-methyl-7aoxa-Sa-B-homoandrostane-3,7-dione. 3-ethylene ketal (I60 g.)in dry tetrahydrofuran (400 ml.) previously cooled to 0 was added l 10ml. of a 1.9 M solution of methyl lithium in diethyl ether. The coolingwas removed and the mixture was allowed to stir at ambient temperaturefor minutes. then it was poured over ice and extracted with ethylacetate. The organic extracts were washed with water, dried (Na SO andevaporated to give l,5-dihydroxy-8,8-ethylenedioxyl,5,l0a,12a-tetramethyl per hydro-1H-benz-[d1- indeno-[4,5-b]-oxepin as awhite solid.

3. The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

4. The suppositories were cooled and removed from molds. They wereindividually wrapped in wax paper for packaging. (Foil may also beused.)

EXAMPLE A suppository was formed in the same manner as in Example 19except that 7-oxa-17B-hydroxy-l7amethyl-5a-androstano-[3,2-c]-pyrazolewas utilized as the active ingredient.

EXAMPLE 21 7-oxal 7B-hydroxyl 7oz-methyl-5a-androstan3-one, 3-ethyleneketal Capsule Formulation 1. 7-oxa-[3-hydroxy-l7a-methyl-Sa-androstan-S-one, 3-ethylene ketal was mixed with thelactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer,

the talc added and blended thoroughly. The mixture was then filled intoNo. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.

EXAMPLE 22 A capsule was formed in the same manner as Example 21 exceptthat 7-oxal 7B-hydroxyl 7a-methyl-5aandrostano-[3,2-cl-pyrazole'wasutilized as the active ingredient.

EXAMPLE 23 7-oxal 7B-hydroxyl 7a-methyl-5a-androstan-3-one, 3-ethyleneketal 0.1 percent Cream 0.1 Percent Cream Mg. Per Gram 7-oxa l7,8hydroxyl 7a-methyl-5aandrostan-B-one. 3-ethylene ketal 1.00 StearylAlcohol l00.0 Cetyl Alcohol I500 White Petrolatum 70.00 MethylParahydroxybenzoate. U.S.P. 2.00 Propyl Parahydroxybenzoate, U.S.P. 0.50lsopropyl Palmitate 60.00 Polyoxyl 40 Stearate. U.S.P. 40.00 PropyleneGlycol 120.00 Disodium Vcrsenate 0. l0 Distilled Water 5)7.l6

Procedure:

3. When the temperature of the ointment reached 55C., a solution of7-oXa-17B-hydroxyl 7a-methyl-5a-andr0stan-3-one, 3-ethylene ketal wasadded and mixed with the ointment.

4. When the temperature of the ointment reached 50C., cold water wascirculated in the jacket of the kettle and the ointment was cooled to30C. with stirring. The ointment was then transferred to storagecontainers.

EXAMPLE 24 A 0.1 percent cream was prepared in the same manner asExample 23 except that 7-oxa-l7B-hydroxyl7a-hydroxyl701-methyl-Sa-androstano-B ,2-c]- pyrazole was utilized as the activeingredient.

EXAMPLE 25 Preparation of 38,17a-dihydroxy-5apregnan-7,20dione diaeetateA solution of 45.73 g. of36,17a-dihydroxypregn-5- en-7,20-dionediacetate in 1.1. of ethyl acetate and 5 ml. of pyridine containing 5 g.of 10 percent by weight palladium on charcoal was shaken in a hydrogenatmosphere at room temperature for 9 hours. The catalyst was removed byfiltration through charcoal and the filandrostano-[3,2-c]-pyrazole wasutilized as the active ingredient.

EXAMPLE l9 7-oxa17B-hydroxy-l7a-methyl-5at-androstan-3-one, 3-ethyleneketal Suppository Formulation Per l.3 Gm.

Suppository 7-oxa-l 7B-hydroxy l 7a-methyl-5aandrostan-3-one, 3-ethyleneketal 0.005 gm. Wecobee M [.250 gm. Carnauba Wax 0.045 gm.

EXAMPLE 28 Preparation of 3B, 17a-dihydroxy-7a-oxa-5a-B-homopregnan-7,20- dione bistrifluoroacetate To0.822 g. (1.5 mmole) of 3B,l7oz-dihydroxy-5apregnan-7,20 -dionebistrifiuoroacetate in 20 ml. of chloroform was added 0.609 g. (3 mmole)of metachloroperbenzoic acid.

After standing at room temperature for 64 hours, 40 ml. of 10 percentsodium sulfite solution was added and stirred for 15 minutes. Theorganic layer was separated and washed with 5 percent by weight aqueoussodium bicarbonate solution, dried (MgSO and concentrated in menu.Crystallization from methylene chloride ether gave 3B, 17a-dihydroxy-7a-oxa-5-B-homopregnan- 7.20-dione bistrifluoroacetate.

EXAMPLE 29 Preparation of 3,8,17a-dihydroxy-7a-oxa-5a-B-homopregnan-7,20-dione bistrifluoroacetate dissolved in 5 ml. of dioxane and 10 ml. ofmethanol was added 0.64 g. of potassium bicarbonate in 4 ml. of water.After stirring for 40 minutes, 10 ml. of water was added and most of thesolvent was removed in vacuo. Water was added and the crystalline solidwas removed by filtration and air dried to yield35,17a-dihydroxy-7a-oxa-5a-B-homopregnan-7,20 dione.

EXAMPLE 30 Preparation of l701-hydroxy-7a-oxa-5a-- B-homopregnan3.7,20-trione.

Chromium trioxide (0.66) g.) was added in portions to 1.5 ml. ofanhydrous pyridine and 50 ml. of methylene chloride with stirring atroom temperature. After stirring for minutes, 0.331 g. of3B,l7a-dihydroxy- 7a-oxa-5a-B-homopregnan-7,20-dione in 50 ml. ofmethylene chloride was added and the reaction mixture was stirred for 30minutes. The dark solution was washed with water, with 1N, HCl, dried(MgSO and the solution was passed through a column of 2 g. of silicagel. Elution with 100 ml. of methylene chloride and 5 then with 100 ml.of 30 percent by volume ethyl acetate in benzene and concentration ofthe combined eluent gave a solid. Crystallization from ethyl acetategave l7a-hydroxy-7a-oxa-5a-B-homopregnan-3,7.20- trione.

EXAMPLE 3].

Preparation of 17ahydroxy-3,3-7,7-20,20-trisethylenedioxy-7aoxa-Sa-B-homopregnane. 15

A solution of 0.1316 g. of l7a-hydroxy-7a-oxa-5wB-homopregnan-3,7,20-trione in 50 ml. of anhydrous benzene, 0.4 ml. ofethylene glycol and 5.2 mg. of p-toluenesulfonic acid monohydrate wasstirred and re- 20 fluxed under a Dean-Stark water separator filled withmolecular sieve 4A for 47 hours. The reaction mixture was washed with 5percent sodium bicarbonate solution, dried (Na SO and concentrated invacuo. Crystallization from methylene chloride diethyl ether gavel7a-hydroxy-3,3-7,7-20,20-trisethylenedioxy-7a-oxa- Sa-B-homopregnane.

EXAMPLE 32 Preparation ofl7a-hydroxy-3,3-20,20-bisethylenedioxy-7a-oxa-5a-B- homopregnan-7-one.

A solution of O. l 30 g. of l7a-hydroxy3,3-7,7-20,20-trisethylenedioxy-7a-oxa-5a-B-homopregnane in 100 ml. of benzenesaturated with water was stirred at room 35 temperature with 10 g. ofanhydrous magnesium sulfate for 2 hours, filtered and concentrated invacuo. Crystallization from methylene chloride-etherhexane gave 17-a-hydroxy-3,3--

EXAMPLE 33 Preparation ofl70z-hydroxy-3,3-20,20-bisethylenedioxy-7a-oxa-5a- I pregnane.

To 1.98 g. (4.4 mmole) of l7a-hydroxy-3,3-20.20-bisethylenedioxy-7a-oxa-5a-B-homopregnan-7-one in ISO ml. of anhydroustetrahydrofuran was added over 20 minutes 13 ml. (21 mmole) of 1.6Mmethyl lithium in diethyl ether with ice bath cooling under a nitrogen-(1,1The cooling bath was removed after l5 minutes and stirring wascontinued at room temperature for lAahours. Water (25 ml.) was addeddropwise and most of the solvent was removed in vacuo. Water was added qand the product which was la,5-dihydroxy-8- ethylenedioxyl 1l-eth-ylenedioxyethyl)- 5,1 OaB, 1ZaB-trimethyl-perhydro-6aoz-bcnz[d]indeno[4,5-b]oxepin was extractedwith ethyl acetate, dried (MgSO and concentrated in vacuo to yield a 0solid. l 1,5-dihydroxy-S-ethylenedioxyl -(l .l ethylenedioxyethyl )-5, lOaB, l ZaB-trimethylperhydro- 6aa-benz[d]indeno[4,5-b]oxepin wasdissolved in 50 ml. of chloroform and I8 ml. of ().7.3M monopcrphthalieacid in diethyl ether was added. The mixture was stirred at roomtemperature for il /z hours, filtered to remove the precipitatedpcrphthalic acid, the filtrate was washed with saturated sodiumbicarbonate solu' tion, dried (Na SO and concentrated to yield IB-(l,l-ethylenedioxyethyl-5-(2-acetoxymethyl-4A- Iethylenedioxy-l-methylcyclohexanyl)-7aB-methyl-3a,4,5,6,7,7a-hexahydroindan-la,4a-diol as a solid. This solid wasdissolved in 80 ml. of ethanol and 3.5 ml.

of ION sodium hydroxide solution was added. The solu-.

tion was refluxed for 40 hours and then concentrated in vacuo. Water wasadded and the product was extracted with methylene chloride, dried (MgSOand concentrated to yield a foam (1.78g.). The crude product wasdissolved in 20 ml. of anhydrous pyridine and treated at roomtemperature with 2.0 g. of ptoluenesulfonyl chloride. After stirring atroom temper- Preparation of l7a-hydroxy-7-oxa-5a-pregnan-3,20-dione.

A solution of 50 mg. of l7oz-hydroxy-3,3-20,20-bisethylenedioxy-7-oxa-5a-pregnane in 2 ml. of methanol and 0.30 ml. ofaqueous 8 percent sulfuric acid (7.) was refluxed for 10 hours. Thesolution was concentrated to dryness in vacuo, water was added and theproduct was extracted with methylene chloride, the extract was dried(MgSO concentrated in vacuo and the product crystallized from methylenechloridediethyl-ether to yield l.7a-hydroxy-7-oxa-5a-pregnan-3,20-dione.

EXAMPLE 35 Preparation of l7a-hydroxy-7-oxapregna- 1 ,4-diene-3,20-dioneacetate.

To a solution of 37 mg. of l7a-hydroxy-7-oxa-5apregnan-3,20-dione in 5ml. of dioxane was added 50 mg. of dichlorodicyanobenzoquinone and 1 mg.of p-toluenesulfonic acid and the solution was heated at reflux for 5hours. The cooled reaction mixture was diluted with methylene chlorideand washed 3 times with 1N aqueous sodium hydroxide and then with water.The extract was dried (MgSO and concentrated in vacuo to yield thel7a-hydroxy-7-oxapregna-l,4-diene- 3,20-dione which was acetylated bytreatment at room temperature with 2.4 ml. of acetic anhydride and 0.01ml. of 72 percent by weight perchloric acid in 25 ml. of anhydrous ethylacetate. The solution was left at room temperature for minutes. washedwith 5 percent by weight aqueous sodium bicarbonate solution, dried(MgSO and concentrated in vacuo. Crystallization of the crude productfrom methylene chloridediethyl ether gave l7a-hydroxy-7-oxapregna-l,4-diene-3,20-dione acetate.

EXAMPLE 36 Preparation of l7a-hydroxy- 7-oxapregn-4-en-3,20-dioneacetate.

A solution of 50 mg. of l7a-hydroxy-7-oxapregnal,4-diene-3,20-acetate in5 ml. of percent by volume ethanol in benzene and 15 mg. oftristriphenylphosphine rhodium chloride was stirred in a uct wasdissolved in benzene and filtered through a col- 'lwa s91199q it 942with? Product crystallized.

' from methylene chloride-diethyl-ether to give17ahydroxy-7-oxapregn-4-en-3 ,20-dione acetate.

EXAMPLE 37 To a solution of7-oxa-l7B-hydroxy-l7a-methyl-5aandrostan-3-one (1.0 g.) in dry pyridine(7 ml.) previously cooled to 0C. was added trifluoroacetic anhy dride(1.0 ml.). The reaction mixture was stirred at 1.0 0-5 for 30 minutesthen was poured into an ice water mixture and acidified with 3Nhydrochloric acid. The resulting precipitate was collected by filtrationand washed with water and then was dissolved in methylene chloride. Thedried solution (Na SO was evaporated in vacuo to give7-oxa-l7/3-hydroxy-l7a-methyl-5aandrostan-3-one, l7-trifluoroa ce tgte V7 EXAMPLE 38 To a solution of 7-oxa-l7B-hydroxy-l7a-methyl-5wandr0stan3-one, l7-trifluoroacetate (3.0 g.) in dioxane (65 ml.)containing p-toluenesulfonic acid (10 mg.) was addeddichlorodicyanobenzoquinone (3.6 g.) and the solution was heated underreflux for 5 hours. The cooled reaction mixture was diluted withmethylene chloride (-200 ml.) and the precipitated hydroquinone wasremoved by filtration. The filtrate was washed 3 times with 1N aqueoussodium hydroxide solution and then with water. The combined organicextracts were dried (Na SO and evaporated to give 2.2 g. of an oil whichwas then dissolved in methanol (50 ml.) containing 10 ml. of 1N sodiumhydroxide solution. After 60 minutes at room temperature, the reactionmixture was diluted with water and extracted with methylene chloride.The organic layers were washed with water, dried (Na SO and concentratedin vacuo to give 1.6 g. of a pale yellow foam. Crystallization of theresidue from methanol furnished 7-oxa-l7/3-hydroxy-l7a-methylandrosta-1,4-dien-3-one, m .p. 183-185C.

EXAMPLE 39 Preparation of I g V 7-oxal 7B-hydroxyl 7a-methylandrostano[2,3d]isoxazole To a solution of7-oxa-2-hydroxymethylene-17amethyl-5a-androstan-3-one (2.7 'g.) inacetic acid (25 ml.) was added a solution of hydroxylamine hydrochloride(0.565 g.) and anhydrous sodium acetate (0.66 g.) in water (2 ml.). Thereaction mixture was heated at -lOOC. for 30 minutes then cooled and theresulting precipitate was collected and washed with acetic acidwater(4:1 parts by volume) and then water. The dried solid was trituratedwith methylene chloride to give 7-oxal 7B-hydroxyl 7a-methylandrostano[2,3d]isoxazole, mp. 302303C.

EXAMPLE 40 Preparation of 7-0xal 7B-hydroxy- 1 7a-methylandrostano [3,2c]

To a solution of 7-oxa-2-hydroxymethylene-17amethyl-Sa-androstan-3-one(2.7 g.) in pyridine (10 ml.) was added a solution of hydroxylaminehydrochloride (1.13 g.) in water (2 ml.) The resulting solution wasrefluxed for 3 hours then cooled and the solvent removed in vacuo. Theresidue was dissolved in ethyl acetate and the organic solution waswashed in turn with 1N hydrochloric acid and water, then dried (Na SOand concentrated to dryness. The crude material (2.4 g.) was dissolvedin dry tetrahydrofuran After standing at room temperature for 60minutes, the organic solution was washed with saturated brine solutionthen dried (Na SO and evaporated in vacuo. Crystallization of theresidue from acetone furnished 7-oxal 7B-hydroxyl 7a-methylandrostano[3,2c]isoxazole, mp. 290-292C.

EXAMPLE 41 Preparation of 7-oxal 7B-hydroxyl 7a-methyl-5 a-androstane Asolution of 7-oxa-l7B-hydroxy-l7a-methyl-5aandrostan-3-one (3.4 g.) and(3 .4 g.) p-toluenesulfonyl hydrazide in methanol (150 ml.) was heatedat reflux for 2 hours. The solution was cooled and sodium borohydride (6g.) was added portionwise, then the reaction mixture was brought toreflux for minutes. Water (10 ml.) was added to the cooled solutionwhich was then concentrated in vacuo. The residual solid was dissolvedin methylene chloride and the organic solution was washed in turn with1N hydrochloric acid, 1N sodium hydroxide and brine then dried (NaSO andevaporated to give crude 7-oxa-l7B-hydroxy-l 7ot-methyl-5aandrostane.Crystallization from methanol gave the pure material, mp. l75-l76C.

EXAMPLE 42 7 Preparation of 7-oxa-3B,l 7B-dihydroxy- 17a-methyl-5a-androstane To a mixture of lithium tri-t-butoxyaluminumhydride (3.0 g.) in dry tetrahydrofuran ml.) previously cooled to O5Cwas added a solution of 7-oxa-,

l'ifl-hydroxyl 7a-methyl-5oz-androstan-3-one in dry tetrahydrofuranml.). After 10 minutes, water (20 ml.) was added and most of the solventremoved in vacuo. The product was extracted with ethyl acetate and theorganic solution was washed with water, dried EXAMPLE 43 Preparation of7-oxa-3B,l 7B-dihydroxyl 7a-methyl-5a-androstane,

3-acetate A solution of 7-oxa-3B,l7B-dihydroxy-l7q-methyl- Sa-androstanein pyridine (5 ml.) containing acetic anhydride (2 ml.) was allowed tostand at room temperature for 16 hours then was diluted. with water. Theresulting solid was collected by filtration, washed with water anddried. Crystallization of the product from diethyl ether furnished7-oxa-3B,l7fi-dihydroxy-l7w methyl-Sa-androstane 3-acetate, m.p.l48-149C.

We claim:

1. A compound of the formula:

wherein R is hydroxy, or hydroxy esterified with trifluoroaceticacid orlower alkanoic acid where the lower alkanoic acid has from 2 to 6 carbonatoms; R is hydrogen or lower alkyl having from 1 to 7 carbon atoms; andR taken together with R from isoxazole. 2. The compound of claim 1wherein said compound is 7-oxa- 1 7B-hydroxyl 7a-methyl-5a-androstano[3,2c]-isoxazoble.

3. The compound of claim 1 wherein said compound is7-oxa-l7,8-hydroxy-17a-methyl-5a-androstano [2,3d1-isoxazole.

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein saidcompound is 7-oxa-17 Beta -hydroxy-17 Alpha -methyl-5 Alpha -androstano(3,2c)-isoxazoble.
 3. The compound of claim 1 wherein said compound is7-oxa-17 Beta -hydroxy-17 Alpha -methyl-5 Alpha -androstano(2,3d)-isoxazole.